Recent years have witnessed an alarming increase in the abuse of methamphetamine (METH), a potent psychomotor stimulant associated with a high incidence of drug relapse in the drug-withdrawn addict. To date, there is no pharmacotherapy that effectively reduces this relapse frequency. The Overall Objective of this grant is to identify putative drug treatments in the pre-clinical setting that can rapidly translate into post-withdrawal pharmacotherapy for the human METH addict. Repeated, intermittent exposure of animals to drugs of abuse causes behavioral and neurobiological changes that may model the neuroadaptive processes that contribute to drug relapse in humans. Behavioral sensitization, characterized by an enduring enhancement in motor behavior that persists for weeks to months after the drug is withdrawn, is common to METH and other drugs of abuse. However, the effects of a behaviorally sensitizing regimen of METH on cellular signaling and gene transcription have not been well studied. Our preliminary data demonstrate that (1) rats behaviorally sensitized to METH exhibit an upregulation of serotonin 5-HT2A/2C receptor -mediated signaling, and (2) post-withdrawal administration of the 5-HT2A/2C antagonist, mianserin, negates the sensitized motor behaviors established by METH. These findings direct our hypotheses that 1) increases in 5-HT2A/2C - function parallels METH-induced behavioral sensitization, and 2) 5-HT2A/2C antagonists can oppose behavioral sensitization and its associated neuroadaptive changes when the antagonists are administered after sensitized responding has developed. Experiments in Aim I will establish a METH dosing paradigm that exhibits an enduring behavioral sensitization (lasting 60 days after withdrawal) with a minimum of neurotoxicity to be used for the remaining studies. Aim II will determine the ability of three clinically available non-selective 5-HT2A/2C antagonists, mianserin, mirtazapine and ketanserin to negate METH-induced behavioral sensitization. The comparative effectiveness of antagonist administration at early and late stages of post-sensitization withdrawal will be ascertained. Aim Ill will establish, across time and brain region, changes in 5-HT receptor signaling, gene transcription (e.g., phosphorylated cAMP response element binding protein) and cellular physiology (e.g., in vivo electrophysiology with microiontophoresis) associated with persistent behavioral sensitization, and its attenuation as caused by post-withdrawal 5-HT antagonist treatments. Aim IV will ascertain the efficacy of newer, 5-HT2A or 5-HT2C -selective antagonists to negate METH-induced behavioral and cellular sensitization. These studies will provide new and important preclinical data for the development of medications targeted towards assisting the drug-withdrawn METH addict to stay drug free.